Alzheimer's disease (AD) is the leading cause of dementia worldwide accounting for around 70% of all cases. There is currently no treatment for AD beyond symptom management and attempts at developing disease-modifying therapies have yielded very little. These strategies have traditionally targeted the peptide Aβ, which is thought to drive pathology. However, the lack of clinical translation of these Aβ-centric strategies underscores the need for diverse treatment strategies targeting other aspects of the disease. Metal dyshomeostasis is a common feature of several neurodegenerative diseases such as AD, Parkinson's disease, and frontotemporal dementia, and manipulation of metal homeostasis has been explored as a potential therapeutic avenue for these diseases. The copper ionophore glyoxalbis-[N4-methylthiosemicarbazonato]Cu(II) (CuII(gtsm)) has previously been shown to improve the cognitive deficits seen in an AD animal model; however, the molecular mechanism remained unclear. Here we report that the treatment of two animal tauopathy models (APP/PS1 and rTg4510) with CuII(gtsm) recovers the cognitive deficits seen in both neurodegenerative models. In both models, markers of tau pathology were significantly reduced with CuII(gtsm) treatment, and in the APP/PS1 model, the levels of Aβ remained unchanged. Analysis of tau kinases (GSK3β and CDK5) revealed no drug induced changes; however, both models exhibited a significant increase in the levels of the structural subunit of the tau phosphatase, PP2A. These findings suggest that targeting the tau phosphatase PP2A has therapeutic potential for preventing memory impairments and reducing the tau pathology seen in AD and other tauopathies.

中文翻译：

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调节蛋白磷酸酶2A可以挽救神经退行性疾病中的疾病表型。

阿尔茨海默氏病（AD）是全世界痴呆症的主要原因，约占所有病例的70％。目前，除了症状治疗外，没有其他针对AD的治疗方法，而开发缓解疾病的疗法的尝试却收效甚微。传统上，这些策略以肽Aβ为靶标，据信该肽可驱动病理。然而，这些以Aβ为中心的策略缺乏临床翻译，突显了针对该疾病其他方面的多种治疗策略的需求。金属动态异常是几种神经退行性疾病（例如AD，帕金森氏病和额颞痴呆）的共同特征，金属动态平衡的研究已被探索为这些疾病的潜在治疗途径。先前已经证明铜离子载体乙二醛-[N4-甲基硫代半碳氮杂] Cu（II）（CuII（gtsm））可以改善AD动物模型中的认知缺陷。然而，其分子机制仍不清楚。在这里，我们报道用CuII（gtsm）处理两种动物tauopathy模型（APP / PS1和rTg4510）可以恢复在两个神经退行性模型中看到的认知缺陷。在两种模型中，tau病理标记物均经过CuII（gtsm）处理后显着降低，而在APP / PS1模型中，Aβ的水平保持不变。tau激酶（GSK3β和CDK5）的分析显示没有药物引起的变化。然而，两个模型都显示出tau磷酸酶PP2A的结构亚基水平显着增加。